This project covers a broad base of studies aimed at assessing the epidemiology of the majority of hormonally-related cancers. Major efforts are underway for breast, endometrial, ovarian, and testicular cancers. We also have an active research program on prostate cancer, covered in a separate report. Our efforts for all of these cancers relate to a variety of environmental, genetic and hormonal predictors of risk. A large multi-disciplinary study is underway in Poland to assess risk factors for breast, ovarian and endometrial cancers. The study involves collection of multiple biologic samples, with a primary aim of assessing the interactive effects of genetic and environmental determinants of risk. In addition, special components of the study are addressing effects of physical activity, occupational factors, and household chemical exposures. For physical activity, special efforts have been expended to improve exposure assessment, with women being asked to wear accelerometers to obtain more objective measures than interview data alone. The study also involves collection of tissue samples to enable precise tumor classification as well as assays of tumor biomarkers (including utilizing newly developed tissue microarray techniques). Another large case-control study, focused on breast cancer, has involved collection of buccal cell specimens. This effort has required extensive methodologic work to determine the optimal means of collecting, processing and storing samples in order to maximize DNA yield. Breast cancer risk is also of major interest in a follow-up of a cohort of women previously screened for bone density. This resource, which previously involved collection of serologic samples and currently is collecting buccal swabs, will enable an assessment of the interrelationship of bone density, genetic factors and endogenous hormones in predicting subsequent cancer occurrence. In addition to breast cancer, several other hormonally-related cancer sites (e.g., endometrium, lung, colorectum) are of interest. We also continue to explore risk factors for breast cancer in a number of case-control studies, including our study in younger women and two studies being conducted in collaboration with extramural investigators (one in China and the other in a cohort of women exposed to polybrominated biphenyls). These studies have been used to explore relationships with menstrual, reproductive, anthrompometric, occupational and chemical risk factors. In addition, in the study of younger women, risk factor differences were sought for tumors defined according to estrogen and receptor hormone status. A collaboration has recently been established with the Gynecologic Oncology Group to determine means of collecting epidemiologic data within the context of a number of ongoing trials. A standardized questionnaire has been developed and plans are underway to integrate this into two large ongoing trials of endometrial and ovarian cancer. This effort should be useful in assessing epidemiologic predictors and molecular markers associated with carefully defined histologic subgroups of tumors, as well as comparing the epidemiology of histologically similar but site diverse tumors. We have learned much about the natural history of cervical cancer (as described in another project report) and are now anxious to expand our knowledge in this area to address the natural history of another gynecologic tumor, namely endometrial cancer. Endometrial hyperplasias are recognized as predisposing to risk but many unresolved questions remain regarding intervening effects of other risk predictors. We have recently launched an exploratory effort within a prepaid health plan to determine the feasility of initiating a larger scale study on the topic. We have recently initiated a large case-control study of testicular cancer in collaboration with the U.S. Department of Defense. A unique resource of banked sera among recent military recruits will enable testing of a variety of pre-diagnostic biologic markers of interest for this tumor, including organochlorines as well as endogenous hormones. As a complement to this research, other studies are being undertaken to identify underlying causes of crptorchism, a recognized risk factor for testicular cancer. Investigations are underway to assess how race and maternal hormone levels influence the risk of this congenital anomaly. Whether there are differences in hormone levels between black and white women is also being pursued, as a means of better understanding racial differences in risk for both crptorchism and testicular cancer. This project has also included a focus on the etiologic role of endogenous hormones for a variety of tumor sites. In these studies, attention is focusing not only on classically accepted hormones, but also on some newly suggested predictors, including insulin-like and other growth factors. An dxtended follow-up of participants in the Columbia, Missouri component of the Mayo Serum Bank is nearing completion; this will allow us to expand upon previous findings and to address newly emerging etiologic hypotheses. We also are developing plans to assess hormone relationships for breast cancer within the etiologic component of the large Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. This resource is unique in having collected multiple biologic samples over time, allowing an assessment of how hormone levels change as patients approach diagnosis. Although cervical cancer has not generally been recognized as a hormonally-related tumor, a number of risk factors, including parity and exogenous hormone use, support the need for further study of hormonal factors. Within the context of a large natural history study, we have assessed the role of endogenous hormones to cervical abnormalities, particularly as they affect the progression and persistance of infection with the human papillomaviruses. Finally, we have conducted research to determine how hormone levels relate to certain genes involved in hormone metabolism. This research has been approached within the Diet Intervention Study of Children and the Portland Cervical Neoplasia Followup Study. Research into the area of metabolites arising from hormone biosynthesis, such as the 2- and 4-hydroxy-codicil estrogens and 16 alpha-hydroxy estrone, has been limited by the lack of suitable laboratory methods to measure these compounds. In light of this, we have established a laboratory at NCI-Frederick, which has led to development of a novel capillary liquid chromatography-mass spectrometry-based analytical method which requires a small volume of urine for complete endogenous estrogen metabolite profiling. The method is currently being expanded to assess a range of other hormones, using other biologic specimens.